Understanding the impact of accelerated release testing conditions on physicochemical properties and drug release mechanisms from etonogestrel implants based on ethylene vinyl acetate

Accelerated release testing is a useful tool for both development and validation of controlled release polymeric implants, as it can shorten development cycles. The objective of this study was to investigate the impact of ethanol and elevated temperature on drug release mechanisms of etonogestrel implants. Based on studies conducted using EVA films, ethanol caused swelling, which increased permeability primarily by increasing solubility while having no impact on polymer crystal structure. Higher temperature caused increased drug release rate but also changed crystal structure. Etonogestrel reservoir implants were manufactured using a two-step double extrusion process. The implant core contained drug dissolved and dispersed in EVA 28 (28% vinyl acetate) while the implant skin consisted of EVA 15 (15% vinyl acetate). In-vitro accelerated release testing revealed a significant change in the curve shape for release through skin, likely due to a rapidly forming solid drug depletion zone in radial direction of the implant core. Pores encapsulating solid drug particles in the implant core contributed to release from ends by increasing apparent permeability. Under accelerated conditions, the drug release mechanism remains governed by diffusion, however the relative rates of drug dissolution and diffusion in the implant core can be impacted by the presence of ethanol.